PROJECT 2 ? Summary: We have determined that the low gastric cancer risk population (LR) at a coastal location in Colombia have considerably higher intestinal parasite burden compared to the higher gastric cancer risk population (HR) residing in the mountains, resulting in a shift from a Th1 proinflammatory response to a downregulated inflammatory Th2 immune response to Helicobacter pylori infection. Further, the intestinal microbiota can colonize the achlorhydric stomach and thereby influence gastric pathogenesis. We will ascertain whether differences in the human gastric microbiota, along with intestinal parasite burden, from low and high risk regions in Colombia and Central American can influence host immune responses and disease outcome, with the aim to provide a new method for stratifying gastric cancer risk. Using mouse models of gastric cancer, we will examine how changes in the human gastric microbiota modulate H. pylori pathogenesis. We will study the mechanism whereby transplanted microflora from HR and LR populations will modulate carcinogenesis in germ-free mice by influencing IL-11 and IL-22 expression. We hypothesize that H. pylori-induced expression of IL-22 may synergize with IL-11 in the induction of epithelial STAT3 activation and exacerbate carcinogenesis. If correct, this would suggest that modulation of IL-11 and IL-22 expression by the microflora could significantly influence disease pathogenesis. To explore the role of individual gastric flora components in additional detail we propose to model the role of parasites using a H. polygyrus co-infection model, and the role of individual bacteria associated with low risk using a co-infection model with a Staphylococcus species that we have found overrepresented in the Columbian LR cohort. We will ask whether these species inhibit carcinogenesis in the H. pylori-infected INS-GAS model and further whether this is associated with inhibition of the IL-22/STAT3 axis.